Regular exercise exerts a profound positive impact on health and the quality of aging. Still, our understanding of the molecular mechanisms that mediate systemic exercise benefits remains surprisingly incomplete. In particular, details of how work in muscle translates to system-wide maintenance, disease deterrence, and even rejuvenation, are too poorly understood to be harnessed for therapeutic applications. We propose to address this knowledge gap from a new angle that features innovative technology, facile gene manipulation, and integrative in vivo neuronal assays over time. We have developed a C. elegans exercise model that uniquely positions us to address three aims that together will advance understanding of the fundamental biology of exercise benefits outside of the muscle domain, with a focus on neuronal aging. Aim 1 will: a) test C. elegans homologs of genes involved in classical mammalian exercise training pathways for roles in strength adaptation, b) address potential requirements for selected stress/longevity pathway genes in exercise-induced enhancement of muscle strength; c) define animal-wide transcription changes that accompany the trained state. Work will establish a deep mechanistic framework for analysis of exercise benefits and address the degree of conservation of exercise adaptation pathways from nematodes to humans. We will firmly ground a novel genetic model in which whole-animal benefits of exercise can be dissected. In Aims 2 and 3, we shift our emphasis to address impact of exercise on neuronal healthspan. Aim 2 will define the impact of exercise on neuronal healthspan while addressing the overall hypothesis that exercise induces functional, structural, and molecular adaptations in neurons, delaying their age-associated decline. We will conduct a detailed analysis of touch receptor neurons, characterizing how exercise changes neuronal function, morphological restructuring, susceptibility to neurotoxic disease protein toxicity, and mitochondrial status over adult life. We will apply selected assays to evaluate additional neuronal types to document in unprecedented cellular detail how exercise influences in vivo nervous system aging. Aim 3 will exploit unique features of the C. elegans experimental system to dissect the tissue network via which genes needed for exercise adaptation promote muscle and neuronal health benefits. We will: a) address whether selected key genes needed for muscle training act autonomously/nonautonomously to impact neuronal healthspan, and b) test exercise-inducible genes encoding secreted proteins for roles in promoting neuronal adaptations. We will gain initial insights into the tissue-interaction circuits involved in system-wide exercise benefits and we may uncover exercise-induced drivers of neuronal healthspan. Given unequivocal evidence that exercise is the most effective anti-aging, anti-disease, pro-health intervention known in medicine, genetic dissection of exercise's maintenance capacities in native context and over time should yield new insights that guide strategies for improving human health and the quality of aging.